Process of producing tocopherollike compounds



UNITED STATES PATENT OFFICE,

PROCESS OF PRODUCING TOCOPHEROL- LIKE COMPOUNDS Lee Irvin Smith, Minneapolis, Minn, assignor to Regents of the University of Minnesota, Minneapolis, Minn., a corporation of Minnesota No Drawing. Original application July 14, 1939,

Serial No. 284,456." Divided and this application January 7, 1943, Serial No. 471,611

16 Claims. (Cl. 260-5333) The present invention relates to methods of It is a further object of the invention to promaking parahydroxy coumarans and chromans, vide a method of making new and useful comand more particularly to methods of making compounds from the metallic salts of substituted I pounds relatedto the tocopherols. P ls having the para position vacant and The invention also relates to themanufacture ben d and 0 P o d S h new compoundsof intermediat whi h ar useful in th produc- It is also an object of the invention to utilize tion of such compounds and separately useful as the herein disclosed procedures and an obvious dyes medieants and t r purposes, variations, extensions and modifications thereof Heretoiore, such parahydroxy chromans and for the Preparation of the yp s 01 compounds coumarans have been prepared by the reaction of 10 herein referred to. hydroquinone compounds, such as alkyl poly It isalso an object of the invention to utilize substituted hydroquinone, with dienes orwith any vknown or hereinafter discovered effects of ailylic halides. Where the hydroquinone comthe described Processes dpr d e o pound of such synthesis has all positions substiother and furtherrobjeets wi l be app rent and tut d except, one position ortho to thehydroxyl implied from the invention described and claimed group, the resultant tocophercl-like compounds are obtained in high yields of great purity, but In ma n para yd y c ro ans and couwhere the hydroquinone compound i u b t marans in accordance with the present'invention, tuted or has more than one vacant position, vari the Starting t rial utiliz d y be y pa ous side reaction products are obtained which are unsubstituted chroman or coumaran. such. s de irabl r those derived from 'the phenols. As represen- According t th present invention, para tatives of these, reference is made to compounds droxy chromans and coumarans'may be prepared Such -D a m hy1 hroman or 2.- from para unsubstituted chromans and coumamethyl eoumaransin h pararans derived from phenolic compounds by the inunsubstituted 01110111941 ren t rn!!! t d t of a hydroxyl radical pan the material, the introduction of the para hydroxyl bridge oxygen, and it is therefore an object of the is acwmplished by $119 8 Procedure, present invention so to prepare such compounds The D ti uted chroma-n or coumaran by u h tho 'is-firsttreated with an aromatic diazoniuni com- Speciflcally, an object is to provide procedures p und such as diazotized sulfanilic acid or diazofor introducing a hydroxyl radical para, to the i d pa nitro n o P uce an intermebridge oxygen of para unsubstituted chromans diabe ale d pound of the invention. This or coumarans by utilizing diazotized aromatic is f"-lllOWed y a reductive. leav ge of the resultcompounds, nitration procedures, or halogenation ant ye P y intermediate, which leads to procedures, v 5 the para amino chroman or coumaran, which It. is an alternative object of the invention to may be n i er s e n ry i r diate. provide a method. of preparing para hydroxy The final step consists in the replacement of the coumarans or chromans by carryingout a series Y amino r up y a hy r xyl roup. r of steps upon ortho allylicphenols, such steps According'to another of such procedures the being carried out in any desired order. The steps 40 para unsubstituted chroman or coumaran is niinclude (1) coupling an ortho allylic phenol havtrated in the para position by any of the usual the D Position w h an ma nitration procedures such as by simultaneous diwmium (2) v at and (3) cunver- Y treatment with sulfuric and nitric acid, or by the sion into the corresponding 9 hydmxy c011" combined reaction with potassiumnitrate d marans or chromans, and it is therefore an obiect of the invention to provide reactions for the sulfunc acid any or these nitration pr dures, the compound undergoing nitration is submi f icludmg h Steps in any desired jected to nitric acid or aderivative thereof which R is a further object or the invention to gives nitric acid in the reaction. The resulting do t 1 making intermediate compounds para mtro chroman or coumaran is then reduced from para unsubstituted chmmans and cow to the corresponding amine by any of the well mar-ans and either aromatic diazonium comknown methods f reducing ni ro mp nds t pounds, and nitrogen containing compounds and. amines. This results in the formation of useful bromo compounds, and to provide such new internitrogen-containing 'chroman (or coumaran) inmediate compounds. termediates. The para amino chroman or coumaran intermediate is then converted to the corresponding para hydroxy compound.

According to a third such method the para unsubstituted chroman or coumaran is halogenated by the use of a bromlnating or chlorinating agent to form the corresponding para halo-chroman (or coumaran). The halogen may be converted to a hydroxyl radical bythe Grignard method, or by direct hydrolysis by an alkaline solution, such as sodium, potassium, calcium or other hydroxides or carbonates or the like, under atmospheric or super atmospheric pressure. Thus, the para halo-chroman (or coumaran) maybe converted into a Grignard reagent by action of metallic magnesium in ethyl ether. The Grignard recompounds as herein set forth but also as a dye and dye intermediate.

Example II A solution is prepared by dissolving 1.25 grams of 2,4,6,7-tetramethyl coumaran': (0.01 mol.) in

. cc. of glacial acetic acid; A second solution is prepared by dissolving 2.5 grams of 2,4-dinitroaniline and 1.5 cc. of cencentrated sulphuric acid agent is then oxidized to the halo-magnesium derivative intermediate of the para hydroxy chroman or coumaran and this is in turn converted into the corresponding para hydroxy chroman or coumaran. i As an alternative to the above'methods, the diazo coupling or nitration or halogenation may be caused to take place with the formation of the corresponding ortho allylic phenol intermediate which is then cyclized, and the resulting para.- azo chroman (or coumaran) or para nitro chroman (or coumaran) or para halo chroman (or coumaran) treated as indicated above .to give the corresponding para hydroxy compounds, or as a further alternative the para-azo or para nitro groups or para halo groups may be replaced by hydroxy groups and the .cyclization caused to take place as the last step.

According to another procedure of the present invention desirable new compounds which are useful for many purposes such as intermediates may be produced by reacting the metallic salts of substituted phenols with carbon dioxide under pressure to form the metallic salts of substituted para hydroxy benzoic acids. Thus the sodium salt or 3,5-dimethyl phenol may be reacted with Two and five-tenths grams of 2,4-dlnitro aniline is diazotized by dissolving in 15 cc, of hot glacial acetic acid 1.5 cc. of concentrated sulphuric acid. The solution is then thoroughly cooled and '1 gram of sodium nitrite addedin small amounts with stirring. An additional 5 cc. of glacial acetic acid is then added to facilitate stirring. The mixture is then admixed with cc. of ethyl ether and decanted for purification.

The thus partially purified diazotized dinitro aniline is then twice redissolved in acetic acid and precipitated for further purification and is finally dissolved in 15' cc. of acetic acid and added to a solution of 2,2,5,8-tetramethyl fi-unsubstituted chroman derived from 2,5-dimethyl phenol, in 5 cc. of acetic. acid. The mixture is allowed to stand for 18 hours, during which time a coupling product precipitates which dissolves in ethyl acetate and crystallizes therefrom. The precipitate is obtained in 130 mg. yield, and has a melting point of about 169-l70 C. This compound is "useful not only for the production of chroman crystallizationfromdilute ethyl alcohol several 1 times and melts at about 6940? C. Four grams of the thus formed 2,2,5,7,8-f

45. pentamethyl-G-bromo chroman and 1.54 grams 1 in 15 cc. of hot glacial acetic acid. The Second solution is cooled to'20 C. in an ice bath and 4 cc. of butyl nitrite are added in 2 cc. portions with continuous shaking. After a few minutes all of the solid material of the second solution is dissolved, and yellow color is produced therein.

Ethyl ether (20 cc.) is then added to the second solution and the diazonium salt which is present in the solution is thereby precipitated by a viscous oil and is separated by decanting off the top rated viscous oily diazoniumsalt is again dissolved in 8 cc. of glacial acetic acid and precipitated with 20 cc. of ether and the oily salt prod not again separated by decanting oil the super layer of the reaction medium. The thus sepanatant layer. The first solution is then admixed with the viscous oily diazonium salt andabright red intermediate product of the present invention precipitates and is separated. The'yield is 3.03 grams and the melting point of the product is' about 174-176 C. before purification.

Example III Two cubic centimeters of bromine in 10 cc. car? hon tetrachloride are added to 5 grams of 35 tetrachloride. Hydrobromic acid is evolved fora period of twenty tothirty minutea'aft'er which period the excess bromine is removed'by shaking with a little aqueous sodium bisulfite, and ethyl 2,2,5,7.8-pentamethyl chroman in 10 cc. of carbon ether is added and the ether-carbon tetrachloride layer is removed. The solvents are pumped. off

and the solid residue (6.2 grams) is purified by ethyl bromide in 12 cc. of ether are dropped slowly into 688 mg. magnesium, the period of dropping being approximately 1 hour; After disappear-j ance of any further visible reaction, the mixture 1 is refluxed for an hour and tank'oxygen is then bubbled through the reaction 'mass for two hours.

Iced hydrochloric acid is added and'the mixture is thoroughly extracted with ethyl ether. The

ether is removed under vacuum leaving aresidual oil which could not be crystallized. The residual oil istaken up with petroleum ether and thoroughly extracted with Claise'n alkali.

kaline extract is diluted with water, acidified-with The alhydrochloric acid and extracted withethyl ether.

Removal of the ether. leaves an oil which" deposits 1 crystals when its solution in dilute, ethyl alcohol is cooled. The thus separated crystalline solid is removed and recrystallized from petroleum ether- It forms large white crystals which weigh 250 1 mg. and have a melting point of about 94--94.5' C. alone and when mixed with an authentic specimen of 2,2,5,7,8 pentamethyl 6 hydroxychroman acid prepared as in Example I,= and a mixture! Example IV I V 2,3,5-trimethyl-6-allyl phenol,-1.73 grains, are dissolved in 7 .9 cc. of 10% sodium hydroxide. To this is added 2.07 grams of *diazotized'sulfanillc.

which thereupon became dark red, is allowed to stand at room temperature for approximately two. hours. To thesolution thereis then added about 4.53 grams of sodium hydro-sulphite and the en tire mixture is heated, with stirring until it reaches 90- C., whereupon it becomes colorless.

To the separated crystalline product thus obtained there is addedan oxidizing solution consisting of 5.5 grams of ferric chloride hexahydrate in 5 cc. of water and 2 cc. of concentratedzhydro chloric acid. Steam is then passed through the mixture, whereupon the quinone compound, which is a liquid, is driven ed and is recovered from the steam distillate by extraction with ethyl ether, 1.43 grams of 2,3,5-trimethyl-6-allyl quinone being obtained.

1.43 grams of the thus produced 2,3,5-trimethyl-6 allyl quinone is converted to 2,3,5-trimethyl-G-allyl hydroquinone by treatment with an excess of zinc in a mixture of 10 grams glacial acetic acid and 3 cc, of water. The mixture of 'quinone, zinc, acetic acid and-water is heated under reflux for 15 minutes and the hydroquinone compound recovered by pouring the refluxed mixture into ice and water, the hydroquinone compound separating in the form of white needlelike crystals. The yield of trimethyl allyl hydroquinone thus formed is 1.16 grams.

The intermediate trimethyl allyl hydroquinone thus produced is cyclized to 2,4,6,'I-tetramethyl- 5-hydroxy coumaran by the following procedure:

One gram of trimethyl allyl hydroquinone and 2 grams pyridinium chloride are heated to a temerature of 205 C. for one hour. The reaction mixture is then dissolved in ethyl ether, the other solution washed with dilute sulphuric acid, and the other layer steam-distilled. The 2,4,63-

tetramethyl-5-hydroxy coumaran distills over and crystallizes out as white needles, the yield being 620 mg. and the melting point being about l29-130 C.

Itwill be noted that the foregoing procedures involve in general the steps of (1) introducing a substituent para to the oxygen and (2) replacement of this substituent by a hydroxyl group in one or more operations. In addition, such of the foregoing procedures as involve the ortho allylic phenols include as a third step (3) cyclization to form the chromans or coumarans. The order in which these steps are carried out is not material, thus providing several alternative routes to the final para hydroxy chromans and coumarans.

The choice of the route taken depends upon the physical properties of the intermediates involved and particularly the yields in each of the steps, and may be widely varied to accommodate the specific materials being operated upon. Thus, the order of the steps may be any order desired with the exception that the Grignard procedure is a procedure such as that in Example III and cannot be applied while the hydroxyl group is present.

These and other obvious variations may be made in any of the procedures herein described and will be understood to be within the purview of the claimed invention.

This application is a division of my application Serial No. 284,456 filed July 14, 1939, now Patent No. 2,331,849 issued October 12, 1943.

I claim:

l. The process which comprises subjecting a chroman having an unsubstituted position para ating agent to form the corresponding P81391181. ogen compound.

2. Theproc ess which comprises subjecting a para-halogentcompoundp 3. The process which comprises subjecting a chroman having an unsubstituted position .para to the bridge oxygen to the action of a chlorinatingagent in a solvent to iorm the correspondingf para-chloro compound.

4. The r'ocess whichcomprises subjecting a.

para unsubstituted coumar an to the action of a brominating agent in a solvent to form the comsponding para-bromo compound.

5. A process or producing a para. hydroxy chroman which comprises converting the prodnot of th process set forth in claim 1 into a Grisnard reagent at .the halogen substituent and then oxidizing said reagent.

6. A process of producing a para hydroxy coumaran which comprises converting to'a hydroxyl group, the halogen group of the product of the process set forth in claim 2.

7. A process of producing a. para hydroxy chroman which comprises hydrolyzing the prodnot of the process or claim 1 with an alkaline reagent.

8. A process of producing a para hydroxy coumaran which comprises hydrolyzing the product I pound selected irom the groupv consisting of para-unsubstituted chromans and coumarans to form the corresponding para-halo compound and replacing the para-halogen substituent of said grou with a hydroxyl group to form the corre-- sponding para-hydroxy tocopherol-like compound..

10. The process of producing tocopherol-Iike compounds which comprises reacting a compound selected from the group consisting of para- 1 unsubstituted chromans and coumarans, to form the corresponding para-halo compound, converting said compound to a Grignard reagent and thenoxidizing and hydrolyzing the so-formed Grignard reagent to liberate the corresponding 7 para-hydroxy tocopherol-like compound.

11. The process of producing tocopherol-like compounds which comprises reacting a compound selected from the group consisting of paramnsubstitutcd chromans and coumarans, to form the corresponding para-halo compound, reacting said para halogen compound with a base and then recovering the so-formed para-hydroxy tocopherol-like compound.

12. The processor producing tocopherol-like compounds which comprises reacting a polyalkyl para-unsubstituted chroman with a halogenating agent to form the corresponding parahalo chroman, and then replacing said para-hal ogen with a hydroxyl group to form the corresponding para-hydroxy tocopherol-like compound.

13. The process of producing tocopherol-like compounds which comprises reacting a poly-alkyl para-unsubstituted chroman with a brominating agent to form the corresponding parabromo chroman, converting the so-formed para: bromochroman into a Grignard reagent, reducing and oxidizing said reagent to yield the to the bridg oxygen tothe action of a halogencorresponding para-hydroxy compound. o

14. Th process of producing tocopherol-like compounds which comprises reacting a poly-a11- kyl para-unsubstituted chroman with a halogen- I ing and purifying th resultant bromochroman tocopherol-like I by crystallization from ethyl alcohol, reacting the A purified bromochroman with ethyl bromide and magnesium under conditions productive 015a;

Grignard of the bromochroman, oxidizing said Grignard to the bromo-magnesium derivative intermediate of the p-hydroxychroman and then converting said derivative to the 2,2,5,7,8-pentamethyl-G-hydroxychroman.

16. The process of producing 2,2,5,7,8-pentamethyl-G-hydroxychromlan which comprises brominating 2,2,'5,7,8-pentamethy1- chroman to introduce a bromo group in the 6 position, and then converting the bromo chroman thus formed into 2,2,5,7,8-pentamethy1-6-hydroxychr0man.1

.LEE IRVIN SMITH. 

